tbuckley/cabot-search huggingface dataset:
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced non-small cell lung cancer.
Authors: HaiPing Xiao, Kai Chen, Yating Zheng, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e21058 Background: Intratumoral heterogeneity (ITH) is associated with the poor prognosis in a variety of solid tumors. However, the use of ITH as a predictive biomarker for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) is still lacking. Methods: We used the Bioconductor R package Maftools to analyze somatic variants of NSCLC from an independent cohort (Hellmman CM012 study cohort) with data from 75 patients with advanced NSCLC. We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and analyzed the correlation with immunogenic marker, and the prognostic effect of ITH on immunotherapy. Results: The objective response rate (ORR) and durable clinical benefit (DCB) of immunotherapy was 36.5% and 53.8% for the patients with low ITH (ITH-L), and 21.7% and 39.1% for the high ITH (ITH-H) subgroup (P = 0.0427, P = 0.3180). The ITH-L patients had significantly improved median progression free survival (mPFS) than the ITH-H group (7.98 versus 2.60 months, hazard ratio (HR) = 1.88, 95%CI 1.06−3.34, P = 0.0280). The ORR and DCB of immunotherapy was 45.9% and 59.5% for the patients with high TMB (TMB-H), and 18.4% and 39.5% for the low TMB (TMB-L) subgroup (P = 0.0354, P = 0.1077). The TMB-H patients had significantly better mPFS than the TMB-L group (8.12 versus 3.78 months, HR = 0.49, 95%CI 0.28−0.87, P = 0.0130). A pooled analysis of ITH and TMB show that mPFS and ORR in the TMB-H+ITH-L group was significantly better than that in the TMB-H+ITH-H, TMB-L+ITH-H, TMB-L+ITH-L group (P = 0.0099, P = 0.0121). A subgroup analysis of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) found that ITH-L was associated with better mPFS (ITH-L versus ITH-H = 8.71 versus 2.17, HR = 3.42, 95%CI 0.96−12.23, P = 0.0460) in LUSC, and no significantly mPFS benefit was found in the ITH-L group in LUAD (ITH-L versus ITH-H = 7.98 versus 5.09, HR = 1.69, 95%CI 0.88−3.26, P = 0.1100). There was no significant difference in TMB levels between ITH-L and ITH-H groups (13.8 Muts/Mb versus 14.2 Muts/Mb, P = 0.2139). Conclusions: ITH may serve as a positive predictor of immunotherapy in patients with advanced NSCLC, especially in LUSC and their clinical value warrants further investigation.
Accounting for the high enrollment of African Americans in Winship Cancer Institute’s myeloma clinical trials.
Authors: Tekiah McClary, Shannon M. Blee, Anna Avinger, Jeffrey M. Switchenko, Margie D. Dixon, Rebecca D. Pentz
Journal: Journal of Clinical Oncology (2022)

12016 Background: Multiple myeloma (MM) is twice as common in African Americans (AA) as in Whites, yet AA make up only 5% of multiple myeloma (MM) clinical trial participants nationwide. Multiple studies have attempted to identify the reasons why AA are underrepresented in clinical trials and have discovered that sociodemographic factors, a lack of understanding, mistrust of sponsors, and a variety of opportunity barriers all contribute to AA underrepresentation in clinical trials. At one cancer center, African Americans make up 33% of those enrolled in MM clinical trials. To begin to account for this success in enrolling AA in myeloma clinical trials, a survey was designed to determine whether the major barriers to AA clinical trial participation existed at this cancer center. Methods: The survey was open to any AA patient who had consented to a clinical trial. The Trust in Medical Research scale (TMR) developed by Hall et al., the Human Connection (THC) scale developed by Mack et al., and the Duke Intrinsic Religiosity Scale (DUREL) were the three main scales used in the survey. Adapted assessment questions from Advani et al were used to assess the importance of side effects in deciding to participate in clinical trials. Results: We offered the study to 76 patients and 80% (61/76) participated. The mean TMR score was 15.0 which is significantly greater than the 11.6 score observed for AAs at other institutions (p &lt; 0.001). The mean human connection score was 57.7 which is significantly greater than the 54.6 observed in the population of the Mack study, which accrued mostly white participants (p &lt; 0.001). The Pearson correlation coefficient between the TMR score and the human connection score is 0.37, indicating a significant positive correlation between human connection scores and trust scores (p-value = 0.002). The average score for the intrinsic religiosity section of the DUREL scale was 13 (score of 15 indicates high religiosity). The average score of importance of side effects was 8.574, significantly higher than the Advani AA response of 6.7 (p-value &lt; 0.001). Conclusions: African Americans enrolled in clinical trials at the high enrolling cancer center had higher THC and TMR scale scores than reported nationally, both helping to facilitate trial enrollment. The high intrinsic religiosity score observed suggests that high religiosity had no impact on clinical trial participation, nor did concern about side effects. Furthermore, a high THC score was associated with a high trust score. Since this THC scale assesses whether participants believe their doctors listen carefully, care about them, offer hope, provide clear explanations, and so on, establishing a human connection may be one way to increase AA trust in providers, increase AA clinical trial enrollment and overcome other barriers.
Analysis of survival and prognostic factors of thymic neuroendocrine tumors.
Authors: Yinggang Mao, Yihui Ma, Xiangke Li, Minjie Yang, Lijie Song
Journal: Journal of Clinical Oncology (2022)

e20622 Background: To investigate the clinical characteristics of thymic neuroendocrine tumors and the relationship between treatment and survival prognosis. Methods: 69 patients, including 54 males and 15 females, who were diagnosed with NETT by puncture or surgical pathology in the First Affiliated Hospital of Zhengzhou University from September 2011 to October 2021 were retrospectively analyzed for initial symptoms, Pathological type, lesion size, treatment and prognosis of survival. Results: The median age of the 69 patients was 53 years old (28-83 years old), the median maximum diameter of the primary lesion was 6.85 cm (1.1-14.9 cm), and the clinical manifestations were not specific. The most common initial symptom was chest tightness and chest pain for 20 cases, 19 cases with hidden disease, found during physical examination. The manifestations of local invasion and metastasis included cough (6 cases), neck and face swelling (9 cases), retrosternal discomfort (3 cases), and low back pain (4 cases). There were 6 cases with systemic manifestations (anorexia, fatigue and fever). Only one case showed ectopic ACTH syndrome. The pathological types included 46 cases of well-differentiated neuroendocrine tumors (5 cases of typical carcinoid tumors, 41 cases of atypical carcinoid tumors), 23 cases of poorly differentiated neuroendocrine tumors (13 cases of small cell carcinomas, 3 cases of large cell neuroendocrine carcinomas, and high-grade neuroendocrine carcinomas). 7 cases of endocrine carcinoma). Masaoka-Koga staging: 2 cases of stage I, 10 cases of stage II, 20 cases of stage III, and 37 cases of stage IV. Thirty patients received surgical treatment, and 19 received postoperative adjuvant therapy. Long-term follow-up results showed a median overall survival time of 49.5 months. Univariate analysis showed that surgery could improve PFS (P = 0.009), while postoperative comprehensive treatment had no effect on PFS (P = 0.724). Pathological grade (P &lt; 0.001), Masaoka-Koga stage (P = 0.004), and surgery (P = 0.014) were associated with OS. Multivariate analysis showed that pathological grade was an independent factor affecting OS (HR: 7.133; 95%CI: 2.183-23.306; P = 0.001). Conclusions: Thymic neuroendocrine tumor is a rare malignant tumor, and pathological grade is an independent risk factor for prognosis. Surgery can improve the patient's PFS.
Rechallenge with immune checkpoint inhibitors beyond severe toxicities, an utopia?
Authors: Laura Medina Rodriguez, Begona Jimenez-Rodriguez, Casilda Llácer, Jose Manuel Manuel Trigo Perez
Journal: Journal of Clinical Oncology (2022)

e14601 Background: Immunotherapy (IO) has substantially improved clinical outcomes in different types of tumours. Its use has been associated with so-called immune-related adverse effects (IrAEs), some of them, potentially severe and/or fatal. Current guidelines recommend discontinuation of IO in severe IrAEs (grades 3/4). Therefore, there is very limited evidence about the safety of “rechallenge” or re-treatment with IO in patients who have experienced severe toxicities. The objective of this study is to describe the toxicities experienced by patients treated with IOs in our unit and identify the recurrence rate of these rEAIs in those patients in whom immunotherapy is re-administered. Methods: We carried out a retrospective analysis of patients treated with IO from January 2015 to April 2021. As inclusion criteria, we selected the condition that the patients have had at least one tumour reevaluation after the IO was started. We have collected clinical and epidemiological variables, efficacy (mesured by RECIST 1.1 and iRECIST criteria) and, as well as recorded toxicity data (mesured by CTCAE V4.3). Results: 220 patients have received some IO drug between the indicated periods. The characteristics of the patients are shown in the attached table. 66% of patients treated with IO have received anti-PD-1/PD-L1 therapy as monotherapy. 60% (134/220) of patients experienced at least 1 IrAE. Of the IrAEs, only 20% were grade 3/4. Only 34 (25%) of the 134 patients who experienced any toxicity required IO stop. Of these 34, only 17 patients achieved retreatment with IO after resolution of initial toxicity. In 14 of the 17 patients who underwent rechallenge, IO was permanently discontinued due to recurrence of the same IrAEs. The IrAE that recurs most frequently after rechallenge was colitis (35% of cases), followed by nephritis (28%). 41% of the patients who experienced toxicity had an objective response to their disease, compared to only 9% in those who did not present any IrAE, which was statistically significant (p&lt;0.05%). Conclusions: In our serie, rechallange with IO after toxicity was associated with the appearance of the same IrAE, which is consistent with what has been published in other series. We are doing further analyses in order to explore IO toxicity deeply, increasing the number of patients which have received immune checkpoint inhibitors.[Table: see text]
Thromboprophylaxis in lung cancer patients with tinzaparin: Results from the investigation on cancer &amp; lung thromboprophylaxis—The iCaLTstudy.
Authors: Marousa Kouvela, Maria Grammoustianou, Foteini Sarropoulou, Maria Mani, Ioannis Gkiozos, Kostas N. Syrigos
Journal: Journal of Clinical Oncology (2022)

e13531 Background: It is known that malignancies exaggerate the risk of thrombosis up to 20%, while for Lung Cancer (LC) is articulated up to 14%. Likewise, thrombosis amplifies the LC progression, thrombosis-associated lung cancer (TALC). The pathophysiology promoting LCAT &amp; TALC is multifactorial depending on the characteristics of LC, specific anti-cancer modalities, patient features, and biomarkers such as tissue factor, neutrophil extracellular traps released in response to cancer, cancer procoagulant, and cytokines. Low-molecular-weight heparins are used in prophylaxis and treatment for high-burden for thrombosis (HTB) patients, allowing specialists to focus on the cancer disease. Methods: iCaLT is a prospective observational study conducted in Thoracic Diseases General Hospital Sotiria (Athens, Greece) assessing the role of thromboprophylaxis with tinzaparin 10.000 Anti-Xa IU, OD with the systemic anti-cancer therapy (SACT). LC patients with active disease that are currently under treatment are enrolled after signing informed consent and monitored up to six months or until anticoagulation terminates. Results: Results from 106 patients reported, 29 (27%) are still ongoing: 79% were males. Histological results involve: adenocarcinomas 54%, squamous 25%, small cell 15%and others. LC patients received SACT: 55%, 23%, 10%, 6% in 1 st , 2 nd , 3 rd and 4 th line. HTB patients with active LC related to 4 factors: disease, treatment, biomarker and patient features are presented in table. On average patients accumulated 3.7±1.1risk factors, 91% of patients accumulated ≥3 risk factors. Median thromboprophylaxis duration was: 4.8 months (1 st -3 rd quartile: 2.8-6.0 months). One patient experienced thrombotic event in lower extremes and consequently pulmonary embolism (efficacy 99.1%, 95%CI: 94.6-99.8%), five patients experienced minor bleeding adverse events (haemoptysis) (4.7%, 95%CI: 2.0-10.6%), and two patients allergic reactions. Patients with haemoptysis had lower age (60 vs. 67, p=0.1357). Conclusions: Thromboprophylaxis with tinzaparin intermediate dose in high thrombotic burden patients with active lung cancer is effective and safe. Further research is needed.[Table: see text]
Clinical utility of urine DNA for noninvasive detection and minimal residual disease monitoring in urothelial carcinoma.
Authors: Zhisong He, Hailong Hu, Yuanjie Niu, Zhaoxia Guo, Feng Ding, Yunkai Wang, Wang Wang, Tao Zhou, Shanbo Cao, Feng Lou, Huina Wang
Journal: Journal of Clinical Oncology (2022)

4583 Background: Current methods for the early detection and minimal residual disease (MRD) of urothelial carcinoma (UC) are often invasive and/or possess sub-optimal sensitivity, especially in upper tract urothelial carcinoma (UTUC). Methods: We developed an efficient workflow named the urine tumor DNA multidimensional bioinformatic predictor, utLIFE, by using low-coverage whole-genome sequencing and targeted deep sequencing. We identified the UC specific mutations and large CNV in the discovery cohort. The utLIFE-UC model was trained in a bladder cancer retrospective cohort (n = 150) and validated in an bladder cohort(n = 674) and UTUC cohort(n = 22). 31 patients established diagnosis of BC who are on neoadjuvant were also enrolled, including a MRD training cohort (n = 16) with serial urine samples at baseline, during treatment and before surgery; a independent MRD validation cohort (n = 15) with urine samples before surgery. Results: The utLIFE-UC model could discriminate UC with high accuracy (94.3%), sensitivity (92.8%), and specificity (96.0%). Furthermore, compared to cytology, the assay achieved a great improvement in sensitivity in the detection of non–muscle-invasive bladder cancer (NMIBC, 94.7% vs. 31.6%,p = 0.0002), and muscle-invasive bladder cancer(MIBC, 82.6% vs. 69.6%, p = 0.4894). The utLIFE-UC model was also validated in independent BC cohort (sensitivity 94.3%, specificity 92.6%) and UTUC cohort (sensitivity 90.9%, specificity 90.9%). utLIFE-UC score also showed outstanding potential on dynamic surveillance of residual disease in UC as the score showed dramatically decreased in pCR patients. As expected, utLIFE-UC score could classify pCR and non-pCR(PR, SD, PD) with NPV 100% in MRD training and validation cohorts, which showed superior sensitivity over that of urine cytology (100% vs.37.5%, p = 0.0070) and FISH (100 vs. 42.9%, p = 0.0125). Conclusions: utLIFE-UC diagnostic model for early diagnosis, residual disease detection in UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind surgery.
Landscape of DNA damage response gene mutations in microsatellite-stable colorectal carcinoma.
Authors: Zhaoyang Zhong, Nan Jiang, Jinming Zhou, Lu Shen, Rongrong Chen
Journal: Journal of Clinical Oncology (2022)

e15558 Background: Colorectal carcinoma (CRC) is one of the most frequent and lethal cancers in the world. Important therapeutic progress of immune checkpoint inhibitors (ICIs) is limited to molecular niche of CRC with microsatellite-stable(MSS). The identification of genomic alterations in the DNA damage response (DDR) pathway have been recognized as pathogenic factors in hereditary cancer predisposition. Few studies showed the effects of ICIs on DDR pathway in patients with MSS CRC. Some reports suggested that DDR could reshape tumor immune microenvironment by regulating tissue repair and local immune response. Here we evaluated the molecular roles of DDR pathway and the immune microenvironment in efficacy of immunotherapy in MSS CRC. Methods: A total of 67 patients with MSS CRC were enrolled into the study. All samples were collected and detected by using NGS with a 1021 gene panel which containing 56 DDR genes (Supplementary table 1). Furthermore, comprehensive bioinformatics analysis were performed by the TCGA and MSK data. We defined pathway alteration as at least one gene in DDR pathway mutated. Results: In our results, three DDR pathway alteration showed poor prognosis (P = 0.0167) compared with DDR wild type in TCGA data (Figure 1A). The MSK data demonstrated that three DDR pathway alteration were associated with a better prognosis in MSS CRC patients through ICIs therapy (P = 0.0416, P = 0.00627, respectively, Figure 1B). The clinical data suggested the patient with DDR pathway alteration had longer OS (354.7 ± 134.0 days, PR) than the others with DDR wild type (247.1± 258.4 days, PD/SD) after PD-1-targeted therapies (P = 1.587e-08). Moreover, the patient with DDR pathway alteration showed significant longer PFS (312.3 ± 179.2 days, PR) compared with DDR wild type (163.3 ± 157.7 days, PD/SD) through immune therapies (P = 4.249e-10). Moreover, significant results of immune infiltrate deconvolution revealed resting memory CD4+ T cells were the most prevalent population between DDR pathway alteration and DDR wild type using CIBERSORT analysis (P = 0.0295, Figure 1C). The activated memory CD4+ T cells in DDR pathway alteration were lower than DDR wild type (P = 0.00858, Figure 1C-D) in patients with MSS CRC. The effects of DDR pathway alteration on immune microenvironment was also necessary for effective PD-1-targeted therapy in future study. Our results suggest that two or more DDR pathways and CD4 + T cells may serve as immunotherapy markers for advanced MSS colorectal cancer. Conclusions: Mutations in DDR pathway may serve as a biomarker for PD-1-targeted therapy through memory CD4+ T cells for MSS CRC patients, which warrants further studies.
Evaluation of outcomes in patients (pts) with stage 4 non-small cell lung cancer (NSCLC 4) harboring actionable oncogenic drivers (AOD) when treated prior to report of mutation without tyrosine kinase inhibitors (TKI): An Integra Connect Database (ICD) retrospective observational study.
Authors: Robert E. Smith, Melissa Lynne Johnson, Lucio N. Gordan, Mei Xue, Prateesh Varughese, Natalie A. Dorrow, Brandon Wang, Varun Vaidya, Mike Gart, Hinco J. Gierman, Jeffrey A. Scott
Journal: Journal of Clinical Oncology (2022)

1530 Background: In a prior analysis, we identified 525 pts with newly diagnosed NSCLC 4 harboring AOD in the ICD. Of these, 141 were treated prior to the reporting of AOD with chemotherapy (C), immune checkpoint inhibitor (ICI), or both. This report details the clinical outcomes of these 141 compared to the 384 treated after AOD reported. Methods: Real world data (RWD) were obtained from a curated ICD for pts with NSCLC 4 diagnosed 1/1/2018-12/31/2020 with cutoff of data 3/31/2021. Pts with EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK were included if their treatment record were captured. Also included were demographics, ECOG score, date of first report of AOD and dates of initiations of first and any second line of therapy and date of apparent death (AD). Outcome measures were time to next treatment or apparent death (TTNT) and apparent survival (AS) (ICD model does not allow date of death per HIPAA de-identified Expert Determination). Descriptive statistics were used with Kaplan-Meier (K-M) estimates and Hazard Ratios (HR) by Cox regression. 3 cohorts were defined: Group (Gr) A with 384 pts treated after AOD reported and used as the comparator; the 141 pts treated before AOD with C, ICI or both were divided into Gr B (n = 51) who subsequently switched to TKI within 35 days and Gr C (n = 90) who did not switch. Results: As shown in data table, AS was significantly worse in Gr B and Gr C, TTNT was significantly worse in Gr C and with worsening trend in Gr B. Two potential confounders were identified: higher ECOG scores might indicate more urgency to assign treatment, but pts with ECOG ≥ 2 were similar in all 3 groups; also, difference in proportion of EGFRm by Group (Gr A 62%, Gr B 57%, and Gr C 29%), but separating cohorts by EGFR mutation status did not alter results. Conclusions: While subject to the limitations of a retrospective observational RWD study, this study strongly suggests outcomes are significantly compromised in pts harboring AOD but who are treated initially with C, ICI or both, even in pts quickly switched to TKI. Since a prospective clinical trial is not ethically feasible, these findings may stimulate review of current guidelines, fuel optimization of universal testing in NSCLC 4, and encourage utilization of liquid or ultra-fast NGS with their rapid turnaround times in order to improve survival in this setting. [Table: see text]